AT(1) receptor antagonist combats oxidative stress and restores nitric oxide signaling in the SHR

The tubuloglomerular feedback (TGF) responses of the spontaneously hyperten sive rat (SHR) are under exaggerated regulation by angiotensin II (Ang II) type 1 receptors (AT(1)-R). Since AT(1)-Rs enhance oxy gen radical (O-2(-)) generation, we tested the hypothesis that the exaggerated TGF was due to a diminished blunting by macula dense (MD)-derived nitric oxide (NO) because of excessive AT(1)-R-dependent generation of O-2(-) Groups Of SHR and cont rol Wistar-Kyoto (WKY) rats received vehicle (Veh), the AT1-R antagonist ca ndesartan (Cand; 3 mg kg(-1) day-l), or nonspecific therapy with hydralazin e + hydrochlorothiazide + reserpine (HHR) for two weeks. Compared with WKY rats, the elevated mean arterial pressure of SHR (WKY 125 +/- 2 vs. SHR 163 to 779 mm Hg, P < 0.001) was reduced (P < 0.001) similarly in SHR by Cand and HHR (121 +/- 5 and 116 +/- 5 mm Hg, P = NS). The SHR had an increased m aximal TGF response (change in stop flow pressure during luminal perfusion of fluid: SHR 11.2 +/- 0.5 vs. WKY 8.3 +/- 0.4 mm Hg, P < 0.01) and a reduc ed TGF response to blockade of neuro-neal NO synthase (nNOS) in the MD with luminal 7-nitro-indazole (7-NI: Delta TGF in WKY 2.8 +/- 0.4 vs. SHR 1.1 /- 0.6 mm Hg, P < 0.05). Although the elevated TGF responses of SHR were no rmalized by both HHR and Cand, only Cand restored a normal TGF response to luminal perfusion of the MD with 7-NI (Delta TGF with 7-NI in SHR: Veh + 1. 8 +/- 0.4 vs. Cand + 3.4 +/- 0.5 mm Hg, P < 0.05). To abrogate the local ef fects of O-2(-), tempol (a membrane-permeable superoxide dismutase mimetic) was perfused into the efferent arteriole. During tempol, SHR given vehicle or HHR had a much increased response to blockade of nNOS with 7-NI (Delta TGF in SHR with 7-NI during tempol: Veh 6.3 +/- 1.0 and HHR 4.5 +/- 0.8 mm Hg, P < 0.01 vs. no tempol for both), implying that the effects of NO had b een prevented because of excessive O-2(-) In contrast, the TGF response to 7-NI in SHR given Cand was unaffected by tempol (Delta TGF with 7-NI during tempol: 2.9 +/- 0.9, P = NS, compared with no tempol). In conclusion, TGF responses of SHR are exaggerated because of the effects of hypertension and AT1-R. AT1-R blockade specifically diminishes oxidative stress and restore s NO signaling in the juxtaglomerular apparatus of the SHR.